Étude atach ii - ssvq · atach ii: but de l’étude ! maintenir une ta systolique horaire...

Étude ATACH II

Jean-Martin Boulanger, Neurologue, HCLM

Conflits d’intérêts

 BI, Sanofi-Aventis, BMS, Roche, Bayer, Novartis, Solvay, Allergan, Merz, Octa-Pharma, Servier

Objectifs  Connaître les résultats de l’étude ATACH II.

 Intégrer dans sa pratique des approches thérapeutiques judicieuses basées sur des données récentes de la littérature.

 Reconnaître les forces et les faiblesses de l’étude ATACH II.

La raison d’être de l’étude  Les hématomes intracérébraux ont tendance à croître dans les

premières heures. Cette croissance est liée à un moins bon devenir clinique.

 La TA augmente en hémorragie cérébrale.

 Une TA élevée a parfois été associée avec une majoration du volume de l’hématome.

 Certaines données suggèrent qu’un traitement agressif de la TA diminue le volume des hématomes. Impact sur le devenir clinique? Cible de TA à viser?

ATACH II: Critères   Hémorragie cérébrale avec

un tx institué en moins de 4.5h et poursuivi ad 24h

  Glasgow Coma Scale ≥ 5 et volume de l’hématome < 60cm3

  Au moins une TA > 180mmHg avant la randomisation

ATACH II: but de l’étude

 Maintenir une TA systolique horaire minimale entre 140-179 mmHg dans le groupe « standard » vs entre 110-139 mmHg dans le groupe « avec traitement agressif » et ce, pour les 24h après la randomisation.

ATACH II: Protocole  Possibilité de recevoir un tx

anti-HTA avant la randomisation si TA > 180mmHg.

 La TA ne devait pas être < 140mmHg avant la randomisation.

ATACH II: Protocole  Après la rando:

 Nicardipine IV 5mg/h  Majoration de 2.5mh/h q 15min ad max 15mg/h

 Si TA demeure au-dessus des cibles après 30 minutes:  Labétalol IV  Diltiazem IV ou Urapidil IV si Labétalol non disponible

ATACH II: Protocole  CT au baseline et à 24h

 Contact téléphonique à 1 mois puis évaluation en personne à 3 mois.

 Évaluateur à l’aveugle du groupe de traitement.

 Issue primaire:  Proportion de patients avec une atteinte fonctionnelle

sévère (MRS 4-6) à 3 mois

ATACH II: Résultats  Début en Mai 2011 et fin en

Septembre 2015.

 110 sites (É-U, Japon, Chine, Taiwan, Corée du Sud et Allemagne).

 8532 patients dépistés et 1000 patients randomisés.

n engl j med 375;11 nejm.org September 15, 2016 1037

Intensive Blood-Pressure Lowering in Acute Cerebr al Hemorrhage

rates of serious adverse events within 3 months after randomization.

R esult s

Participant PopulationThe trial enrolled the first patient in May 2011 and the last in September 2015. We conducted the trial at 110 sites in the United States, Japan, China, Taiwan, South Korea, and Germany. A total of 8532 patients were screened, of whom 1000 under-

went randomization; 500 patients were assigned to the intensive-treatment group and 500 to the standard-treatment group (Fig. S1 in the Supple-mentary Appendix). The mean age of the enrolled patients was 61.9 years. A total of 38.0% of the patients were women, and 56.2% of the patients were Asian. The mean (±SD) systolic blood pres-sure at baseline was 200.6±27.0 mm Hg. The demo-graphic and clinical characteristics of the partici-pants at baseline, which are shown in Table 1, were similar in the two treatment groups.

CharacteristicIntensive Treatment

(N = 500)Standard Treatment

(N = 500)

Age — yr 62±13.1 61.9±13.1

Male sex — no. (%) 304 (60.8) 316 (63.2)

Race — no. (%)†

Asian 277 (55.4) 285 (57.0)

Black 73 (14.6) 58 (11.6)

White 142 (28.4) 145 (29.0)

Other or unknown 8 (1.6) 12 (2.4)

Hispanic ethnic group — no. (%)† 38 (7.6) 41 (8.2)

Recruited at site in Asia — no. (%) 264 (52.8) 273 (54.6)

Glasgow Coma Scale score — no. (%)‡

3–11 73 (14.6) 74 (14.8)

12–14 152 (30.4) 142 (28.4)

15 275 (55.0) 284 (56.8)

Systolic blood pressure at presentation in emergency department — mm Hg§

200±27.1 201.1±26.9

Median NIHSS score (range)¶ 11 (0–40) 11 (0–40)

Intracerebral hematoma volume

>30 cm3 — no./total no. (%) 45/496 (9.1) 51/492 (10.4)

Median (range) — cm3∥ 10.3 (2.3–85.2) 10.2 (0.98–79.1)

Intraventricular hemorrhage — no./total no. (%) 122/496 (24.6) 142/492 (28.9)

Location of hemorrhage — no./total no. (%)

Thalamus 193/496 (38.9) 180/492 (36.6)

Basal ganglia 255/496 (51.4) 251/492 (51.0)

Cerebral lobe 48/496 (9.7) 60/492 (12.2)

Cerebellum 0/496 1/492 (0.2)

* Plus–minus values are means ±SD. There were no significant differences between the two groups at baseline.† Race and ethnic group were self-reported. Asian race included patients enrolled in Asian countries and non-Asian countries.‡ The Glasgow Coma Scale score (range, 3 to 15), a measure of level of consciousness, is a scale that quantifies response

in three components, with a score of 3 indicating deep unconsciousness and higher scores indicating milder impair-ment of consciousness.

§ Data were missing for 1 patient in the standard-treatment group.¶ The National Institutes of Health Stroke Scale (NIHSS), a serial measure of neurologic deficit, is a 42-point scale that

quantifies neurologic deficits in 11 categories, with a score of 0 indicating normal function without neurologic deficit and higher scores indicating greater severity of deficit. Data were missing or were obtained outside the specified time window for 30 patients in the intensive-treatment group and for 41 in the standard-treatment group.

∥ Hematoma volume was measured by a central reader. The rapid assessment of the hematoma volume by the site in-vestigator was used to determine eligibility.

Table 1. Demographic and Clinical Characteristics of the Participants, According to Treatment Group.*

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITE DE SHERBROOKE on October 3, 2016. For personal use only. No other uses without permission.

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ATACH II: Résultats  Temps moyen sx-rando = 182.2 min (groupe

intensif) vs 184.7 min (groupe standard)

 TA horaire moyenne des 2 premières heures = 128.9mmHg (intensif) vs 141.1 mmHg (standard)

 Taux d’échec au:  Premier traitement = 12.2% vs 0.8% (p<0.001)  Deuxième traitement = 15.6% vs 1.4% (p<0.001)

n engl j med 375;11 nejm.org September 15, 20161038

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

InterventionThe mean interval between symptom onset and randomization was 182.2±57.2 minutes in the intensive-treatment group and 184.7±56.7 minutes in the standard-treatment group (Table S1 in the Supplementary Appendix). The mean values of hourly minimum systolic blood pressure for the first 24 hours after randomization according to treatment group are shown in Fig. 1. The mean minimum systolic blood pressure during the first 2 hours was 128.9±16 mm Hg in the intensive-treatment group and 141.1±14.8 mm Hg in the standard-treatment group.

Primary treatment failure occurred in 61 pa-tients (12.2%) in the intensive-treatment group versus 4 (0.8%) in the standard-treatment group (P<0.001); secondary treatment failure occurred in 78 patients (15.6%) in the intensive-treatment group versus 7 (1.4%) in the standard-treatment group (P<0.001). Among patients who died, with-drawal of care was reported in 61% (20 of 33) of those in the intensive-treatment group and in 76% (26 of 34) in the standard-treatment group.

OutcomesAmong the 961 participants in whom the pri-mary outcome was ascertained, death or disabil-ity was observed in 186 participants (38.7%) in the intensive-treatment group and in 181 (37.7%) in the standard-treatment group (Table 2). In the primary analysis that used the multiple-imputa-tion method for the 39 participants with missing outcome data, the relative risk was 1.04 (95%

confidence interval [CI], 0.85 to 1.27), with ad-justment for age, initial GCS score, and presence or absence of intraventricular hemorrhage. The prespecified sensitivity analysis that used the worst-case imputation yielded a relative risk of 1.04 (95% CI, 0.85 to 1.26). There was no signifi-cant between-group difference in the ordinal distribution of the modified Rankin scale score at 3 months (Fig. 2). The post hoc proportional-odds logistic-regression analysis yielded a com-mon odds ratio of 1.07 (P = 0.56) without viola-tion of assumption of proportionality of the odds. Analysis of the primary outcome according to prespecified subgroups showed no significant differences (Fig. 3). In addition, neither the EQ-5D measures nor the percentages of patients with hematoma expansion differed significantly be-tween the treatment groups (Table 2).

There were no significant between-group dif-ferences in the rate of death at 3 months or in neurologic deterioration at 24 hours after ran-domization. The percentage of patients with treatment-related serious adverse events within 72 hours after randomization was 1.6% in the intensive-treatment group and 1.2% in the stan-dard-treatment group. However, the percentage of patients with any serious adverse event during the 3 months after randomization was higher in the intensive-treatment group than in the standard-treatment group (25.6% vs. 20.0%; adjusted rela-tive risk, 1.30; 95% CI, 1.00 to 1.69; P = 0.05) (Table 2). Lists of adverse events and serious ad-verse events, according to treatment group, are provided in Tables S2 and S3, respectively, in the Supplementary Appendix.

Table S4 in the Supplementary Appendix lists adverse events and serious adverse events that were related to renal function, cardiac function, brain hemorrhage, and brain infarction after randomization. The rate of renal adverse events within 7 days after randomization was signifi-cantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P = 0.002). There was no significant differ-ence in the rates in any of the other adverse-event groups.

Discussion

The ATACH-2 trial was discontinued for futility before we reached the target enrollment of 1280 participants. The absolute difference between the

Figure 1. Mean Hourly Minimum Systolic Blood Pressure during the First 24 Hours after Randomization, According to Treatment Group.

The dashed vertical line indicates 2 hours, and I bars 95% confidence intervals.

Min

imum

Sys

tolic

Blo

od P

ress

ure

(mm

Hg)

160

140

150

130

120

00 5 10 15 20 25

Hours since Randomization

Standard treatment

Intensive treatment



Analyse post hoc: Taux de complications rénales à 7 jours plus important dans le groupe intensif: 9.0% vs 4.0% (p 0.002) mais pas de différence pour les complications rénales sérieuses (0.8À% vs 0.2%-p= 0.1804)

n engl j med 375;11 nejm.org September 15, 20161040

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

two groups in the rate of death or disability was 1 percentage point. The trial was powered to identify a difference in risk of 10 percentage points or more with intensive treatment as com-pared with standard treatment, because a small-er difference in risk was expected to be viewed as insufficient for broad acceptance of a new inter-vention.5 A higher proportion of patients with primary treatment failure was observed in the intensive-treatment group than in the standard-treatment group, and perhaps the treatment ef-fect would have been greater if the treatment goals had been met in a higher proportion of participants.

In the subgroup analysis (Fig. 3), the relative risk of death or disability with intensive treat-ment as compared with standard treatment was 1.02 among participants who met the specified target within 2 hours after randomization and 0.61 among those who did not meet the speci-fied target. However, the test for interaction was not significant, and the precision of relative-risk estimates is too wide to make any definitive conclusions.

The recruitment window was extended dur-

ing the trial on the basis of evidence that an intensive reduction in the systolic blood-pressure level could benefit participants who were treated between 3 and 4.5 hours after symptom onset. A time-dependent loss of benefit of intensive reduction in the systolic blood-pressure level in participants who were recruited between 3 and 4.5 hours after symptom onset is possible, al-though it was not observed in the subgroup analysis of INTERACT2.5 A relatively high pro-portion of Asian participants were recruited in our trial, although the percentage was lower than that in INTERACT2. However, there was no sig-nificant difference in treatment effect between Asian patients and non-Asian patients in our trial or between participants recruited in China and those recruited in other countries in INTERACT2.5

Our trial incorporated the prerandomization use of intravenous antihypertensive agents to en-sure timely compliance with existing guidelines,16 but this strategy may have obscured the effec-tiveness of the trial intervention. The observed rate of death or disability at 3 months in the standard-treatment group (37.7%) was lower than the rate that was anticipated in the trial design on the basis of previous literature (60%).6,19,20 A high percentage of patients with favorable characteristics at baseline (e.g., 56% of the pa-tients had a baseline GCS score of 15) may have conferred a predisposition to a favorable out-come in our trial sample regardless of treatment (ceiling effect), making it difficult to discern the beneficial effect of an intensive reduction in the systolic blood-pressure level in this trial.6 The high proportion of favorable outcomes may also have resulted from the monitoring and standardizing intensity of medical care provided at each site and a low rate of withdrawal of care among participants recruited in the trial (as compared with a 34% rate outside clinical trials).21

There were several key differences between INTERACT2 and the ATACH-2 trial. An estimated 41% of the participants in INTERACT2 under-went randomization 4 or more hours after symp-tom onset, whereas all the participants in the ATACH-2 trial underwent randomization and were treated within 4.5 hours after symptom on-set. In INTERACT2,5 only 48% of the 2839 par-ticipants underwent randomization with an initial systolic blood pressure of 180 mm Hg or more, whereas all the participants in the ATACH-2 trial had an initial systolic blood pressure of

Figure 2. Distribution of Scores on the Modified Rankin Scale, According to Treatment Group.

The data are presented only for participants for whom a score on the modi-fied Rankin scale score was obtained at 90 days. The percentage of partici-pants with each score on the modified Rankin scale is shown in or above each cell. Scores range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability (able to carry out all usual activities, despite some symptoms), 2 slight disability (able to look after own affairs without assistance but unable to carry out all previous activities), 3 moderate dis-ability (requires some help but able to walk unassisted), 4 moderately se-vere disability (unable to attend to bodily needs without assistance and un-able to walk unassisted), 5 severe disability (requires constant nursing care and attention, bedridden, and incontinent), and 6 death. Percentages may not sum to exactly 100.0 owing to rounding.

0 1 2 3 4 5 6

0 20 40 60 80 100

Percent of Patients

Standard Treatment(N=480)

Intensive Treatment(N=481)

7.1 19.6 17.3 18.3 26.5

4.2 7.1

5.8

26.017.519.119.8

5.0 6.9

Score on the Modified Rankin Scale



Étude cessée pour futilité avant le 1280 patients souhaités

n engl j med 375;11 nejm.org September 15, 2016 1041

Intensive Blood-Pressure Lowering in Acute Cerebr al Hemorrhage

180 mm Hg or more. Primary treatment failure was seen in 66% of the participants within 1 hour after randomization in INTERACT2 and in 12.2% of those in the intensive-treatment group within 2 hours after randomization in the ATACH-2 trial.

In our trial, the mean minimum systolic blood

pressure in the first 2 hours after randomization was 128.9 mm Hg in the intensive-treatment group and 141.1 mm Hg in the standard-treatment group. In INTERACT2, the mean systolic blood pressure was 150 mm Hg in the first hour in the intensive-treatment group and 164 mm Hg in the

Figure 3. Unadjusted Relative Risk of Death or Disability at 3 Months, According to Subgroup.

The Glasgow Coma Scale is a measure of level of consciousness, with a score of 3 indicating deep unconsciousness and higher scores indicating milder impairment of consciousness; scores range from 3 to 15. The data are presented only for participants for whom a score on the modified Rankin scale score was obtained at 90 days. Data were missing on the following characteristics: on presence or absence of intraventricular hemorrhage for 4 patients in the intensive-treatment group and 7 in the standard-treatment group; on base-line hematoma volume for 4 in the intensive-treatment group and 7 in the standard-treatment group; on location of hematoma for 4 in the intensive-treatment group and 7 in the standard-treatment group; and on presence or absence of type 2 diabetes mellitus for 10 in the intensive-treatment group and 7 in the standard-treatment group. Data on location of hematoma are not shown for 1 patient in the intensive-treatment group whose hematoma was in the cerebellum (no patient in the standard-treatment group had a hematoma in this location). Data for patients with other or unknown race are not shown. The size of the squares is proportional to the precision of the estimates.

0.50 1.0 4.002.00

Standard Treatment BetterIntensive Treatment Better

Glasgow Coma Scale score3–1112–1415

Intraventricular hemorrhageYesNo

Baseline hematoma volume>30 cm3

≤30 cm3

Hematoma locationBasal gangliaCerebral lobeThalamus

Type 2 diabetes mellitusYesNo

Met systolic blood pressure target within 2 hrYesNo

SexMaleFemale

RaceAsianBlackWhite

Hispanic ethnic groupYesNo

Enrolled at Asian siteYesNo

Relative Risk (95% CI)Subgroup

0.95 (0.74–1.21)

0.96 (0.54–1.69)1.03 (0.87–1.22)

1.09 (0.84–1.42)1.22 (0.81–1.86)

1.15 (0.92–1.44)0.88 (0.70–1.10)

0.92 (0.73–1.17)

0.61 (0.26–1.43)1.02 (0.87–1.21)

1.00 (0.84–1.20)1.09 (0.75–1.59)

0.92 (0.74–1.15)

1.06 (0.83–1.35)1.16 (0.65–2.06)

1.04 (0.86–1.25)

1.00 (0.79–1.26)

0.95 (0.73–1.22)

1.14 (0.95–1.37)

0.97 (0.73–1.28)

0.90 (0.71–1.14)

1.09 (0.89–1.34)

0.25

1.16 (0.90–1.49)

P Value forInteraction

143278540

253697

91859

486104359

166778

90160

595366

555117269

74887

532429

0.62

0.53

0.73

0.75

0.75

0.51

0.20

0.60

0.84

0.49

No. ofPatients



Discussion-Conclusion  En hémorragie cérébrale <24h, il n’y a pas de

bénéfice à traiter une TA systolique > 180 mmHg.

 Aucune différence selon les sous-groupes.

  Il s’agit toutefois d’une étude sur les hématomes de relatif petits-moyens volumes affectant surtout les structures profondes. Peu de données sur les hématomes lobaires.

 Étude plus « hyperaiguë » qu’INTERACT II, plus «hypertensive» et moins d’échecs au traitement.

Conclusion  « Lower is not better. »

 On vise moins de 180 mmHg de systolique en hémorragie cérébrale pour les premières 24h, pas davantage.

Étude atach ii - ssvq · atach ii: but de l’étude ! maintenir une ta systolique horaire...

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